This invention relates to a method and a formulation for orally administering a bioactive agent encapsulated in one or more biocompatible polymer or copolymer excipients, preferably a biodegradable polymer or copolymer, affording microcapsules which due to the proper size of the resultant microcapsules results in the agent reaching and being taken up by the folliculi lymphatic aggregati, otherwise known as the "Peyer's patch," or "GALT" of the animal without loss of effectiveness due to the agent having passed through the gastrointestinal tract. Similar folliculi lymphatic aggregati can be found in the bronchei tubes (BALT) and the large intestine. Hereafter, the above-described tissues are referred to in general as mucosally associated lymphoreticular tissues.
The use of microencapsulation to protect sensitive bioactive agents from degradation has become well-known. Typically, a bioactive agent is encapsulated within a protective wall material, usually polymeric in nature. The agent to be encapsulated can be coated with a single wall of polymeric material (microcapsules), or can be homogeneously dispersed within a polymeric matrix (microspheres). (Hereafter, the term microcapsules refers to both microcapsules and microspheres). The amount of agent inside the microcapsule can be varied as desired, ranging from either a small amount to as high as 95% of the microcapsule composition. The diameter of the microcapsule can also be varied as desired, ranging from less than one micrometer to as large as three millimeters or more.
Peyer's patches are conglomerations of lymphoid nodules located in the illeum or lower part of the intestine, and are an important part of the body's defense against bacterial infection. Antigens are substances that promote antibody formation, and include such things as foreign protein or tissue. All antibodies belong to a class of proteins call immunoglobulins (Ig). When an antibody and antigen combine, they form an inactive complex, thus neutralizing the antigen.
Peyer's patches possess IgA precursor B cells which can populate the lamina propria regions of the gastrointestinal and upper respiratory tracts and differentiate into mature IgA synthesizing plasma cells. It is these plasma cells which actually secrete the antibody molecules. Studies by Heremans and Bazin measuring the development of IgA responses in mice orally immunized with antigen showed that a sequential appearance of antigen-specific IgA plasma cells occurred, first in mesenteric lymph nodes, later in the spleen, and finally in the lamina propria of the gastrointestinal tract (Bazin, H., Levi, G., and Doria, G. Predominant contribution of IgA antibody-forming cells to an immune response detected in extraintestinal lymphoid tissues of germfree mice exposed to antigen via the oral route. J. Immunol. 105: 1049; 1970 and Crabbe, P. A., Nash, D. R., Bazin, H. Eyssen, H., and Heremans, J. F. Antibodies of the IgA type in intestinal plasma cells of germfree mice after oral or parenteral immunization with ferritin. J. Exp. Med. 130: 723; 1969) It is apparent, therefore, that Peyer's patches are enriched sources of precursor IgA cells, which, subsequent to antigen sensitization, follow a circular migrational pathway and account for the expression of IgA at distant mucosal surfaces. This circular pattern provides a common mucosal immune system by continually transporting sensitized B cells to mucosal sites for responses to gut-encountered environmental antigens and potential pathogens.
Of particular importance to the present invention is th ability of oral immunization to induce protective antibodies. It is known that the ingestion of antigens by animals results in the appearance of antigen-specific secretory IgA antibodies in bronchial or nasal washings. For example, studies with human volunteers show that oral administration of influenza vaccine is effective at inducing secretory anti-influenza antibodies in nasal secretions.
It is apparent that any method or formulation involving oral administration of an ingredient be of such design that will protect the agent from degradation during its passage through the gastrointestinal tract. If not, the ingredient will reach the Peyer's patch, if at all, in an inadequate quantity or ineffective condition. In unprotected form large quantities of the bioactive agent must be taken for an effective amount of the agent to reach the Peyer's patch. The result is that a large percentage of the administered agent is unused. Also, frequent oral administrations are necessary to achieve a prolonged delivery of agent to the Peyer's patch. Such frequent administration of high doses of agent is both wasteful and inconvenient.
Therefore, there exists a need for a method of oral immunization which will effectively stimulate the mucosal immune system and overcome the problem of degradation of the bioactive ingredient during its passage through the gastrointestinal tract to the Peyer's patch. There exists a more particular need for a method of targeting an antigen to the Peyer's patch and releasing that antigen once in the Peyer's patches.